L-Glutamate is thought to be the major excitatory neurotransmitter in the vertebrate central nervous system and is known to activate at least three major, pharmacologically distinct classes of glutamate-gated ion channels: N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and kainate receptors. These three inotropic receptors are named according to their selective agonists.
NMDA receptors have attracted particular attention because of their importance in normal brain function and in pathophysiological conditions such as epilepsy and cerebral ischemia (Rothman, S. M. and Olney, J. W., Trends Neurosci., 10:299-302 (1987)). The NMDA receptor appears to be essential for the induction of long-term potentiation (Collingridge, G. L. and Bliss, T. V. P., Trends Neurosci., 10:288-293 (1987)), a proposed underlying mechanism for learning and memory (Madison, D. V., et al., Annu. Rev. Neurosci., 14:379-397 (1991)), ischemic cell death, epilepsy, and other neurological disorders (Simon, R. P., et al., Science 226:850-852 (1984); Choi, D. W., J. Neurosci. 10:2493-2501 (1990) such as hypoxic neuronal damage (Simon, R., et al., Science, 226:850-852 (1984)), schizophrenia (Carlsson, M., et al., Trends Neurosci., 13:272-276 (1990); Watchel, H., et al., Trends Pharmacol. Sci., 11:219-220 (1990)) and excitotoxicity (Onley, J., et al., Brain Res., 221:207-210 (1981)). The integral channel of the NMDA receptor is permeable to Na+, K+, and Ca.sup.2+. NMDA receptor activation thus increases intracellular Ca.sup.2+ in neuronal cells, and this process is thought to evoke glutamate-induced neurotoxicity (Madison, D. V., et al., Annu. Rev. Neurosci., 14:379-397 (1991)).
Thus, inhibition of NMDA receptor activity would be useful for protecting against various disorders including glutamate-induced neurotoxicity.